Proteasome inhibition has emerged as a viable mode of anti-cancer therapy (Orlowski and Kuhn, 2008, Clin. Cancer Res. 14, 1649-1657). Proteasome inhibitors induce apoptosis by preventing degradation of pro-apoptotic proteins, thereby facilitating activation of programmed cell death. With such pro-cancer effects, proteasome inhibitors, such as bortezomib, have found use in cancer therapy.
Inhibition of the proteasome induces new proteasome synthesis promoted by transcription factors. This transcriptional feedback mechanism is conserved in mammals and ensures that proteasome activity is matched to demand. Proteasome inhibition followed by proteasome gene upregulation is referred to as the proteasome “bounce-back” response.
As reported (Mitsiades, N., et al. 2002, Proc Natl Acad Sci, 99, 14374-14379), inhibition of the proteasome leads to upregulation of the proteasome (PSM) genes. As shown in FIGS. 1A-1C, human prostate cancer (LNCaP) and colon cancer (HT29) cell lines that were treated with different proteasome inhibitors (MG132, YU101, and bortezomib) induced transcription of several PSM genes that encode members of both the 20S (PSMA7, PSMB4, and PSMB7) and 19S (PSMC1, PSMC4, PSMD1, and PSMD12) complexes.
While some proteasome inhibitors dissociate from the proteasome allowing proteasome activity to resume (e.g. bortezomib), other proteasome inhibitors (e.g. YU101, carfilzomib) bind the proteasome irreversibly, such that proteasome recovery is solely dependent on new synthesis of proteasome genes. Furthermore, both bortezomib (an FDA-approved drug for the treatment of multiple myeloma) and carfilzomib (an experimental therapeutic) are rapidly cleared from the patients' blood within the first hour of their administration (Papandreou et al., 2004, J. Clin. Oncol., 22, 2108-2121; Schwartz and Davidson, 2004, Oncology, (Williston Park), 19, (14, Suppl. 11), 14-21). Therefore, once the drug is cleared, proteasome activity recovers through a combination of the drug dissociating from the active site and new proteasome synthesis.
The extent and duration of proteasome inhibition that is achieved with bortezomib has been shown to be sufficient to kill many multiple myeloma tumor cells, but that does not ensure that bortezomib is sufficient for other cancers. In fact, bortezomib has shown limited efficacy in certain cancers, and resistance to bortezomib has also been observed (Orlowski and Kuhn, 2008). Accordingly, there is a need for improved cancer therapies through enhanced proteasome inhibition and prevention of induced proteasome synthesis.